Inherent specificities in natural antibodies: a key to immune defense against pathogen invasion

Abstract

Natural antibodies are produced at tightly regulated levels in the complete absence of external antigenic stimulation. They provide immediate, early and broad protection against pathogens, making them a crucial non-redundant component of the humoral immune system. These antibodies are produced mainly, if not exclusively, by a subset of long-lived, self-replenishing B cells termed B-1 cells. We argue here that the unique developmental pattern of these B-1 cells, which rests on positive selection by self antigens, ensures production of natural antibodies expressing evolutionarily important specificities that are required for the initial defense against invading pathogens. Positive selection for reactivity with self antigens could also result in the production of detrimental anti-self antibodies. However, B-1 cells have evolved a unique response pattern that minimizes the risk of autoimmunity. Although these cells respond rapidly and strongly to host-derived innate signals, such as cytokines, and to pathogen-encoded signals, such as lipopolysaccharide and phosphorylcholine, they respond very poorly to receptor-mediated activation. In addition, they rarely enter germinal centers and undergo affinity maturation. Thus, their potential for producing high-affinity antibodies with harmful anti-self specificity is highly restricted. The positive selection of B-1 cells occurs during the neonatal period, during which the long-lived self-renewing B-1 population is constituted. Many of these cells (B-1a) express CD5, although a smaller subset (B-1b) does not express this surface marker. Importantly, B-1a cells should not be confused with short-lived anergic B-2 cells, which originate in the bone marrow in adults and initiate CD5 expression and programmed cell death following self-antigen recognition. In summary, we argue here that the mechanisms that enable natural antibody production by B-1 cells reflect the humoral immune system, which has evolved in layers whose distinct developmental mechanisms generate complementary repertoires that collectively operate to maximize flexibility in responses to invading pathogens. B-2 cells, present in what may be the most highly evolved layer(s), express a repertoire that is explicitly selected against self recognition and directed towards the generation of high-affinity antibody response to external antigenic stimuli. B-1 cells, whose repertoire is selected by recognition of self antigen, belong to what may be earlier layer(s) and inherently maintain production of evolutionarily important antibody specificities that respond to pathogen-related, rather then antigen-specific signals.

Enhanced IgA Class Switching in Marginal Zone and B1 B Cells Relative to Follicular/B2 B Cells

“…These observations, together with our results, suggest that B1 cells undergo poor class switching in general, with the noted exception of IgA (which is still only 14% at most). This inefficient class switching is consistent with the fact that B1 cells are the source of natural serum IgM (38).…”

Class switching and consecutive loss of dsDNA‐reactive B1a B cells from the peritoneal cavity during murine lupus development

“…They have a low activation threshold and have been reported to spontaneously secrete IgM antibodies in vitro and in vivo [3,4]. Although B1a cells normally express IgM, they have been shown to be able to class switch to IgG and other isotypes [5].…”

Division and differentiation of natural antibody-producing cells in mouse spleen

“…Although found mainly in peritoneal and pleural cavities in adults, small numbers of these cells are present in the spleen, where they express a phenotype similar to the peritoneal B-1a cells but lack the CD11b surface determinant that most of the peritoneal B-1a cells express. Much of the innate in vivo antibody response to systemic bacterial stimuli such as LPS has been shown to be produced by B-1a cells and/or their plasma cell progeny in the spleen (1).…”

“…B-1 ͉ CD138 ͉ CD5 ͉ lipopolysaccharide ͉ plasma cells B -1a cells, which give rise to cells that produce most of the natural antibodies found in mouse serum, have unique localization and development patterns and display unique activation requirements (1)(2)(3). Although found mainly in peritoneal and pleural cavities in adults, small numbers of these cells are present in the spleen, where they express a phenotype similar to the peritoneal B-1a cells but lack the CD11b surface determinant that most of the peritoneal B-1a cells express.…”